Skip to main content

Advertisement

SpringerLink
Log in

RNA-biology ruling cancer progression? Focus on 3′UTRs and splicing

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

The protein-coding regions of mRNAs have the information to make proteins and hence have been at the center of attention for understanding altered protein functions in disease states, including cancer. Indeed, the discovery of genomic alterations and driver mutations that change protein levels and/or activity has been pivotal in our understanding of cancer biology. However, to better understand complex molecular mechanisms that are deregulated in cancers, we also need to look at non-coding parts of mRNAs, including 3′UTRs (untranslated regions), which control mRNA stability, localization, and translation efficiency. Recently, these rather overlooked regions of mRNAs are gaining attention as mounting evidence provides functional links between 3′UTRs, protein functions, and cancer-related molecular mechanisms. Here, roles of 3′UTRs in cancer biology and mechanisms that result in cancer-specific 3′-end isoform variants will be reviewed. An increased appreciation of 3′UTRs may help the discovery of new ways to explain as of yet unknown oncogene activation and tumor suppressor inactivation cases in cancers, and provide new avenues for diagnostic and therapeutic applications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Article 20 October 2020

Gregory J. Goodall & Vihandha O. Wickramasinghe

References

  1. Nangalia, J., & Campbell, P. J. (2019). Genome sequencing during a patient’s journey through cancer. The New England Journal of Medicine, 381(22), 2145–2156. https://doi.org/10.1056/NEJMra1910138.

    Article  CAS  PubMed  Google Scholar 

  2. Carninci, P., Kasukawa, T., Katayama, S., Gough, J., Frith, M. C., Maeda, N., et al. (2005). The transcriptional landscape of the mammalian genome. Science, 309(5740), 1559–1563. https://doi.org/10.1126/science.1112014.

    Article  CAS  PubMed  Google Scholar 

  3. Huang, Q., Yan, J., & Agami, R. (2018). Long non-coding RNAs in metastasis. Cancer Metastasis Reviews, 37(1), 75–81. https://doi.org/10.1007/s10555-017-9713-x.

    Article  CAS  PubMed  Google Scholar 

  4. Anastasiadou, E., Jacob, L. S., & Slack, F. J. (2018). Non-coding RNA networks in cancer. Nature Reviews. Cancer, 18(1), 5–18. https://doi.org/10.1038/nrc.2017.99.

    Article  CAS  PubMed  Google Scholar 

  5. Yang, E., van Nimwegen, E., Zavolan, M., Rajewsky, N., Schroeder, M., Magnasco, M., & Darnell JE Jr. (2003). Decay rates of human mRNAs: Correlation with functional characteristics and sequence attributes. Genome Research, 13(8), 1863–1872. https://doi.org/10.1101/gr.1272403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sharova, L. V., Sharov, A. A., Nedorezov, T., Piao, Y., Shaik, N., & Ko, M. S. (2009). Database for mRNA half-life of 19 977 genes obtained by DNA microarray analysis of pluripotent and differentiating mouse embryonic stem cells. DNA Research, 16(1), 45–58. https://doi.org/10.1093/dnares/dsn030.

    Article  CAS  PubMed  Google Scholar 

  7. Friedel, C. C., & Dölken, L. (2009). Metabolic tagging and purification of nascent RNA: Implications for transcriptomics. Molecular BioSystems, 5(11), 1271–1278. https://doi.org/10.1039/b911233b.

    Article  CAS  PubMed  Google Scholar 

  8. Eser, P., Demel, C., Maier, K. C., Schwalb, B., Pirkl, N., Martin, D. E., Cramer, P., & Tresch, A. (2014). Periodic mRNA synthesis and degradation co-operate during cell cycle gene expression. Molecular Systems Biology, 10, 717. https://doi.org/10.1002/msb.134886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gerstberger, S., Hafner, M., & Tuschl, T. (2014). A census of human RNA-binding proteins. Nature Reviews. Genetics, 15(12), 829–845. https://doi.org/10.1038/nrg3813.

    Article  CAS  PubMed  Google Scholar 

  10. Lunde, B. M., Moore, C., & Varani, G. (2007). RNA-binding proteins: Modular design for efficient function. Nature Reviews. Molecular Cell Biology, 8(6), 479–490. https://doi.org/10.1038/nrm2178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hentze, M. W., Castello, A., Schwarzl, T., & Preiss, T. (2018). A brave new world of RNA-binding proteins. Nature Reviews. Molecular Cell Biology, 19(5), 327–341. https://doi.org/10.1038/nrm.2017.130.

    Article  CAS  PubMed  Google Scholar 

  12. Lewis, B. P., Burge, C. B., & Bartel, D. P. (2005). Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell, 120(1), 15–20. https://doi.org/10.1016/j.cell.2004.12.035.

    Article  CAS  PubMed  Google Scholar 

  13. Paulsen, M. T., Veloso, A., Prasad, J., Bedi, K., Ljungman, E. A., Tsan, Y. C., Chang, C. W., Tarrier, B., Washburn, J. G., Lyons, R., Robinson, D. R., Kumar-Sinha, C., Wilson, T. E., & Ljungman, M. (2013). Coordinated regulation of synthesis and stability of RNA during the acute TNF-induced proinflammatory response. Proceedings of the National Academy of Sciences of the United States of America, 110(6), 2240–2245. https://doi.org/10.1073/pnas.1219192110.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Cannell, I. G., Merrick, K. A., Morandell, S., Zhu, C. Q., Braun, C. J., Grant, R. A., Cameron, E. R., Tsao, M. S., Hemann, M. T., & Yaffe, M. B. (2015). A pleiotropic RNA-binding protein controls distinct cell cycle checkpoints to drive resistance of p53-defective tumors to chemotherapy. Cancer Cell, 28, 623–637. https://doi.org/10.1016/j.ccell.2015.09.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Medford, R. M., Nguyen, H. T., & Nadal-Ginard, B. (1983). Transcriptional and cell cycle-mediated regulation of myosin heavy chain gene expression during muscle cell differentiation. The Journal of Biological Chemistry, 258(18), 11063–11073.

    CAS  PubMed  Google Scholar 

  16. Hitti, E., Iakovleva, T., Brook, M., Deppenmeier, S., Gruber, A. D., Radzioch, D., Clark, A. R., Blackshear, P. J., Kotlyarov, A., & Gaestel, M. (2006). Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element. Molecular and Cellular Biology, 26(6), 2399–2407. https://doi.org/10.1128/MCB.26.6.2399-2407.2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Abdelmohsen, K., & Gorospe, M. (2010). Posttranscriptional regulation of cancer traits by HuR. Wiley Interdisciplinary Reviews RNA, 1(2), 214–229. https://doi.org/10.1002/wrna.4.

    Article  CAS  PubMed  Google Scholar 

  18. Sengupta, S., Jang, B. C., Wu, M. T., Paik, J. H., Furneaux, H., & Hla, T. (2003). The RNA-binding protein HuR regulates the expression of cyclooxygenase-2. The Journal of Biological Chemistry, 278(27), 25227–25233. https://doi.org/10.1074/jbc.M301813200.

    Article  CAS  PubMed  Google Scholar 

  19. Torun, A., Enayat, S., Sheraj, I., Tunçer, S., Ülgen, D. H., & Banerjee, S. (2019). Butyrate mediated regulation of RNA binding proteins in the post-transcriptional regulation of inflammatory gene expression. Cellular Signalling, 64, 109410. https://doi.org/10.1016/j.cellsig.2019.109410.

    Article  CAS  PubMed  Google Scholar 

  20. Levine, A. J. (1997). p53, the cellular gatekeeper for growth and division. Cell, 88(3), 323–331. https://doi.org/10.1016/s0092-8674(00)81871-1.

    Article  CAS  PubMed  Google Scholar 

  21. Hollstein, M., Sidransky, D., Vogelstein, B., & Harris, C. C. (1991). p53 mutations in human cancers. Science, 253(5015), 49–53. https://doi.org/10.1126/science.1905840.

    Article  CAS  PubMed  Google Scholar 

  22. Soussi, T., & Wiman, K. G. (2007). Shaping genetic alterations in human cancer: The p53 mutation paradigm. Cancer Cell, 12(4), 303–312. https://doi.org/10.1016/j.ccr.2007.10.001.

    Article  CAS  PubMed  Google Scholar 

  23. Morandell, S., Reinhardt, H. C., Cannell, I. G., Kim, J. S., Ruf, D. M., Mitra, T., Couvillon, A. D., Jacks, T., & Yaffe, M. B. (2013). A reversible gene-targeting strategy identifies synthetic lethal interactions between MK2 and p53 in the DNA damage response in vivo. Cell Reports, 5(4), 868–877. https://doi.org/10.1016/j.celrep.2013.10.025.

    Article  CAS  PubMed  Google Scholar 

  24. Reinhardt, H. C., Hasskamp, P., Schmedding, I., Morandell, S., van Vugt, M. A., Wang, X., et al. (2010). DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization. Molecular Cell, 40(1), 34–49. https://doi.org/10.1016/j.molcel.2010.09.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rosenstierne, M. W., Vinther, J., Mittler, G., Larsen, L., Mann, M., & Norrild, B. (2008). Conserved CPEs in the p53 3′ untranslated region influence mRNA stability and protein synthesis. Anticancer Research, 28(5A), 2553–2559.

    CAS  PubMed  Google Scholar 

  26. Vilborg, A., Glahder, J. A., Wilhelm, M. T., Bersani, C., Corcoran, M., Mahmoudi, S., Rosenstierne, M., Grandér, D., Farnebo, M., Norrild, B., & Wiman, K. G. (2009). The p53 target Wig-1 regulates p53 mRNA stability through an AU-rich element. Proceedings of the National Academy of Sciences of the United States of America, 106(37), 15756–15761. https://doi.org/10.1073/pnas.0900862106.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Mazan-Mamczarz, K., Galbán, S., López de Silanes, I., Martindale, J. L., Atasoy, U., Keene, J. D., et al. (2003). RNA-binding protein HuR enhances p53 translation in response to ultraviolet light irradiation. Proceedings of the National Academy of Sciences of the United States of America, 100(14), 8354–8359. https://doi.org/10.1073/pnas.1432104100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ahuja, D., Goyal, A., & Ray, P. S. (2016). Interplay between RNA-binding protein HuR and microRNA-125b regulates p53 mRNA translation in response to genotoxic stress. RNA Biology, 13(11), 1152–1165. https://doi.org/10.1080/15476286.2016.1229734.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Liu, L., Ouyang, M., Rao, J. N., Zou, T., Xiao, L., Chung, H. K., Wu, J., Donahue, J. M., Gorospe, M., & Wang, J. Y. (2015). Competition between RNA-binding proteins CELF1 and HuR modulates MYC translation and intestinal epithelium renewal. Molecular Biology of the Cell, 26(10), 1797–1810. https://doi.org/10.1091/mbc.E14-11-1500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mukherjee, N., Jacobs, N. C., Hafner, M., Kennington, E. A., Nusbaum, J. D., Tuschl, T., Blackshear, P. J., & Ohler, U. (2014). Global target mRNA specification and regulation by the RNA-binding protein ZFP36. Genome Biology, 15(1), R12. https://doi.org/10.1186/gb-2014-15-1-r12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kuwano, Y., Nishida, K., Kajita, K., Satake, Y., Akaike, Y., Fujita, K., Kano, S., Masuda, K., & Rokutan, K. (2015). Transformer 2β and miR-204 regulate apoptosis through competitive binding to 3′ UTR of BCL2 mRNA. Cell Death and Differentiation, 22(5), 815–825. https://doi.org/10.1038/cdd.2014.176.

    Article  CAS  PubMed  Google Scholar 

  32. Hennig, J., & Sattler, M. (2015). Deciphering the protein-RNA recognition code: Combining large-scale quantitative methods with structural biology. Bioessays, 37(8), 899–908. https://doi.org/10.1002/bies.201500033.

    Article  CAS  PubMed  Google Scholar 

  33. Cho, S. J., Zhang, J., & Chen, X. (2010). RNPC1 modulates the RNA-binding activity of, and cooperates with, HuR to regulate p21 mRNA stability. Nucleic Acids Research, 38(7), 2256–2267. https://doi.org/10.1093/nar/gkp1229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Torres-Fernández, L. A., Jux, B., Bille, M., Port, Y., Schneider, K., Geyer, M., Mayer, G., & Kolanus, W. (2019). The mRNA repressor TRIM71 cooperates with nonsense-mediated decay factors to destabilize the mRNA of CDKN1A/p21. Nucleic Acids Research, 47(22), 11861–11879. https://doi.org/10.1093/nar/gkz1057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kurosaki, T., Popp, M. W., & Maquat, L. E. (2019). Quality and quantity control of gene expression by nonsense-mediated mRNA decay. Nature Reviews. Molecular Cell Biology, 20(7), 406–420. https://doi.org/10.1038/s41580-019-0126-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Park, J., Seo, J. W., Ahn, N., Park, S., Hwang, J., & Nam, J. W. (2019). UPF1/SMG7-dependent microRNA-mediated gene regulation. Nature Communications, 10(1), 4181. https://doi.org/10.1038/s41467-019-12123-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kim, Y. K., & Maquat, L. E. (2019). UPFront and center in RNA decay: UPF1 in nonsense-mediated mRNA decay and beyond. RNA, 25(4), 407–422. https://doi.org/10.1261/rna.070136.118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bartel, D. P. (2004). MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 116(2), 281–297.

    Article  CAS  PubMed  Google Scholar 

  39. Erson, A. E., & Petty, E. M. (2008). MicroRNAs in development and disease. Clinical Genetics, 74(4), 296–306. https://doi.org/10.1111/j.1399-0004.2008.01076.x.

    Article  CAS  PubMed  Google Scholar 

  40. Tuna, M., Machado, A. S., & Calin, G. A. (2016). Genetic and epigenetic alterations of microRNAs and implications for human cancers and other diseases. Genes, Chromosomes & Cancer, 55(3), 193–214. https://doi.org/10.1002/gcc.22332.

    Article  CAS  Google Scholar 

  41. Gebert, L. F. R., & MacRae, I. J. (2019). Regulation of microRNA function in animals. Nature Reviews. Molecular Cell Biology, 20(1), 21–37. https://doi.org/10.1038/s41580-018-0045-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Peng, Y., & Croce, C. M. (2016). The role of MicroRNAs in human cancer. Signal Transduction and Targeted Therapy, 1, 15004. https://doi.org/10.1038/sigtrans.2015.4.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Teige, I., Mårtensson, L., & Frendéus, B. L. (2019). Targeting the antibody checkpoints to enhance cancer immunotherapy-focus on FcγRIIB. Frontiers in Immunology, 10, 481. https://doi.org/10.3389/fimmu.2019.00481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hermeking, H. (2007). p53 enters the microRNA world. Cancer Cell, 12(5), 414–418.

    Article  CAS  PubMed  Google Scholar 

  45. Zhang, L., Liao, Y., & Tang, L. (2019). MicroRNA-34 family: A potential tumor suppressor and therapeutic candidate in cancer. Journal of Experimental & Clinical Cancer Research, 38(1), 53. https://doi.org/10.1186/s13046-019-1059-5.

    Article  Google Scholar 

  46. Slabáková, E., Culig, Z., Remšík, J., & Souček, K. (2017). Alternative mechanisms of miR-34a regulation in cancer. Cell Death & Disease, 8(10), e3100. https://doi.org/10.1038/cddis.2017.495.

    Article  CAS  Google Scholar 

  47. Chen, P. C., Yu, C. C., Huang, W. Y., Huang, W. H., Chuang, Y. M., Lin, R. I., et al. (2019). c-MYC acts as a competing endogenous RNA to sponge. Cancers (Basel), 11(10). https://doi.org/10.3390/cancers11101457.

  48. Szostak, E., & Gebauer, F. (2013). Translational control by 3'-UTR-binding proteins. Briefings in Functional Genomics, 12(1), 58–65. https://doi.org/10.1093/bfgp/els056.

    Article  CAS  PubMed  Google Scholar 

  49. Uniacke, J., Holterman, C. E., Lachance, G., Franovic, A., Jacob, M. D., Fabian, M. R., Payette, J., Holcik, M., Pause, A., & Lee, S. (2012). An oxygen-regulated switch in the protein synthesis machinery. Nature, 486(7401), 126–129. https://doi.org/10.1038/nature11055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Szostak, E., García-Beyaert, M., Guitart, T., Graindorge, A., Coll, O., & Gebauer, F. (2018). Hrp48 and eIF3d contribute to msl-2 mRNA translational repression. Nucleic Acids Research, 46(8), 4099–4113. https://doi.org/10.1093/nar/gky246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Arake de Tacca, L. M., Pulos-Holmes, M. C., Floor, S. N., & Cate, J. H. D. (2019). PTBP1 mRNA isoforms and regulation of their translation. RNA, 25(10), 1324–1336. https://doi.org/10.1261/rna.070193.118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mazumder, B., Sampath, P., & Fox, P. L. (2005). Regulation of macrophage ceruloplasmin gene expression: One paradigm of 3'-UTR-mediated translational control. Molecules and Cells, 20(2), 167–172.

    CAS  PubMed  Google Scholar 

  53. Ray, P. S., & Fox, P. L. (2007). A post-transcriptional pathway represses monocyte VEGF-A expression and angiogenic activity. The EMBO Journal, 26(14), 3360–3372. https://doi.org/10.1038/sj.emboj.7601774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Arif, A., Yao, P., Terenzi, F., Jia, J., Ray, P. S., & Fox, P. L. (2018). The GAIT translational control system. Wiley Interdisciplinary Reviews RNA, 9(2), e1441. https://doi.org/10.1002/wrna.1441.

    Article  CAS  Google Scholar 

  55. Ostareck, D. H., Ostareck-Lederer, A., Wilm, M., Thiele, B. J., Mann, M., & Hentze, M. W. (1997). mRNA silencing in erythroid differentiation: hnRNP K and hnRNP E1 regulate 15-lipoxygenase translation from the 3′ end. Cell, 89(4), 597–606. https://doi.org/10.1016/s0092-8674(00)80241-x.

    Article  CAS  PubMed  Google Scholar 

  56. Friend, K., Campbell, Z. T., Cooke, A., Kroll-Conner, P., Wickens, M. P., & Kimble, J. (2012). A conserved PUF-Ago-eEF1A complex attenuates translation elongation. Nature Structural & Molecular Biology, 19(2), 176–183. https://doi.org/10.1038/nsmb.2214.

    Article  CAS  Google Scholar 

  57. Waerner, T., Alacakaptan, M., Tamir, I., Oberauer, R., Gal, A., Brabletz, T., Schreiber, M., Jechlinger, M., & Beug, H. (2006). ILEI: A cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells. Cancer Cell, 10(3), 227–239. https://doi.org/10.1016/j.ccr.2006.07.020.

    Article  CAS  PubMed  Google Scholar 

  58. Chaudhury, A., Hussey, G. S., Ray, P. S., Jin, G., Fox, P. L., & Howe, P. H. (2010). TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nature Cell Biology, 12(3), 286–293. https://doi.org/10.1038/ncb2029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hussey, G. S., Chaudhury, A., Dawson, A. E., Lindner, D. J., Knudsen, C. R., Wilce, M. C., et al. (2011). Identification of an mRNP complex regulating tumorigenesis at the translational elongation step. Molecular Cell, 41(4), 419–431. https://doi.org/10.1016/j.molcel.2011.02.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Vicario, A., Colliva, A., Ratti, A., Davidovic, L., Baj, G., Gricman, Ł., Colombrita, C., Pallavicini, A., Jones, K. R., Bardoni, B., & Tongiorgi, E. (2015). Dendritic targeting of short and long 3' UTR BDNF mRNA is regulated by BDNF or NT-3 and distinct sets of RNA-binding proteins. Frontiers in Molecular Neuroscience, 8, 62. https://doi.org/10.3389/fnmol.2015.00062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Melendez, J., Grogg, M., & Zheng, Y. (2011). Signaling role of Cdc42 in regulating mammalian physiology. The Journal of Biological Chemistry, 286(4), 2375–2381. https://doi.org/10.1074/jbc.R110.200329.

    Article  CAS  PubMed  Google Scholar 

  62. Ciolli Mattioli, C., Rom, A., Franke, V., Imami, K., Arrey, G., Terne, M., Woehler, A., Akalin, A., Ulitsky, I., & Chekulaeva, M. (2019). Alternative 3' UTRs direct localization of functionally diverse protein isoforms in neuronal compartments. Nucleic Acids Research, 47(5), 2560–2573. https://doi.org/10.1093/nar/gky1270.

    Article  CAS  PubMed  Google Scholar 

  63. Katz, Z. B., Wells, A. L., Park, H. Y., Wu, B., Shenoy, S. M., & Singer, R. H. (2012). β-Actin mRNA compartmentalization enhances focal adhesion stability and directs cell migration. Genes & Development, 26(17), 1885–1890. https://doi.org/10.1101/gad.190413.112.

    Article  CAS  Google Scholar 

  64. Rodriguez, A. J., Shenoy, S. M., Singer, R. H., & Condeelis, J. (2006). Visualization of mRNA translation in living cells. The Journal of Cell Biology, 175(1), 67–76. https://doi.org/10.1083/jcb.200512137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gutierrez, N., Eromobor, I., Petrie, R. J., Vedula, P., Cruz, L., & Rodriguez, A. J. (2014). The β-actin mRNA zipcode regulates epithelial adherens junction assembly but not maintenance. RNA, 20(5), 689–701. https://doi.org/10.1261/rna.043208.113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kislauskis, E. H., Zhu, X., & Singer, R. H. (1994). Sequences responsible for intracellular localization of beta-actin messenger RNA also affect cell phenotype. The Journal of Cell Biology, 127(2), 441–451. https://doi.org/10.1083/jcb.127.2.441.

    Article  CAS  PubMed  Google Scholar 

  67. Hüttelmaier, S., Zenklusen, D., Lederer, M., Dictenberg, J., Lorenz, M., Meng, X., Bassell, G. J., Condeelis, J., & Singer, R. H. (2005). Spatial regulation of beta-actin translation by Src-dependent phosphorylation of ZBP1. Nature, 438(7067), 512–515. https://doi.org/10.1038/nature04115.

    Article  CAS  PubMed  Google Scholar 

  68. Gu, W., Pan, F., & Singer, R. H. (2009). Blocking beta-catenin binding to the ZBP1 promoter represses ZBP1 expression, leading to increased proliferation and migration of metastatic breast-cancer cells. Journal of Cell Science, 122(Pt 11), 1895–1905. https://doi.org/10.1242/jcs.045278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gu, W., Katz, Z., Wu, B., Park, H. Y., Li, D., Lin, S., Wells, A. L., & Singer, R. H. (2012). Regulation of local expression of cell adhesion and motility-related mRNAs in breast cancer cells by IMP1/ZBP1. Journal of Cell Science, 125(Pt 1), 81–91. https://doi.org/10.1242/jcs.086132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Nwokafor, C. U., Sellers, R. S., & Singer, R. H. (2016). IMP1, an mRNA binding protein that reduces the metastatic potential of breast cancer in a mouse model. Oncotarget, 7(45), 72662–72671. https://doi.org/10.18632/oncotarget.12083.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Niedner, A., Edelmann, F. T., & Niessing, D. (2014). Of social molecules: The interactive assembly of ASH1 mRNA-transport complexes in yeast. RNA Biology, 11(8), 998–1009. https://doi.org/10.4161/rna.29946.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Martin, K. C., & Ephrussi, A. (2009). mRNA localization: Gene expression in the spatial dimension. Cell, 136(4), 719–730. https://doi.org/10.1016/j.cell.2009.01.044.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Mili, S., Moissoglu, K., & Macara, I. G. (2008). Genome-wide screen reveals APC-associated RNAs enriched in cell protrusions. Nature, 453(7191), 115–119. https://doi.org/10.1038/nature06888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wong, H. H., Lin, J. Q., Ströhl, F., Roque, C. G., Cioni, J. M., Cagnetta, R., et al. (2017). RNA docking and local translation regulate site-specific axon remodeling in vivo. Neuron, 95(4), 852–868.e8. https://doi.org/10.1016/j.neuron.2017.07.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Preitner, N., Quan, J., Nowakowski, D. W., Hancock, M. L., Shi, J., Tcherkezian, J., Young-Pearse, T. L., & Flanagan, J. G. (2014). APC is an RNA-binding protein, and its interactome provides a link to neural development and microtubule assembly. Cell, 158(2), 368–382. https://doi.org/10.1016/j.cell.2014.05.042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bergsten, S. E., & Gavis, E. R. (1999). Role for mRNA localization in translational activation but not spatial restriction of nanos RNA. Development, 126(4), 659–669.

    CAS  PubMed  Google Scholar 

  77. Zaessinger, S., Busseau, I., & Simonelig, M. (2006). Oskar allows nanos mRNA translation in Drosophila embryos by preventing its deadenylation by Smaug/CCR4. Development, 133(22), 4573–4583. https://doi.org/10.1242/dev.02649.

    Article  CAS  PubMed  Google Scholar 

  78. Berkovits, B. D., & Mayr, C. (2015). Alternative 3' UTRs act as scaffolds to regulate membrane protein localization. Nature, 522(7556), 363–367. https://doi.org/10.1038/nature14321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Jaiswal, S., Jamieson, C. H., Pang, W. W., Park, C. Y., Chao, M. P., Majeti, R., et al. (2009). CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell, 138(2), 271–285. https://doi.org/10.1016/j.cell.2009.05.046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ma, W., & Mayr, C. (2018). A membraneless organelle associated with the endoplasmic reticulum enables 3'UTR-mediated protein-protein interactions. Cell, 175(6), 1492–1506.e19. https://doi.org/10.1016/j.cell.2018.10.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Grabowski, P. J., Seiler, S. R., & Sharp, P. A. (1985). A multicomponent complex is involved in the splicing of messenger RNA precursors. Cell, 42(1), 345–353. https://doi.org/10.1016/s0092-8674(85)80130-6.

    Article  CAS  PubMed  Google Scholar 

  82. Berget, S. M., Moore, C., & Sharp, P. A. (1977). Spliced segments at the 5′ terminus of adenovirus 2 late mRNA. Proceedings of the National Academy of Sciences of the United States of America, 74(8), 3171–3175. https://doi.org/10.1073/pnas.74.8.3171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Chow, L. T., Gelinas, R. E., Broker, T. R., & Roberts, R. J. (1977). An amazing sequence arrangement at the 5′ ends of adenovirus 2 messenger RNA. Cell, 12(1), 1–8. https://doi.org/10.1016/0092-8674(77)90180-5.

    Article  CAS  PubMed  Google Scholar 

  84. Fica, S. M., & Nagai, K. (2017). Cryo-electron microscopy snapshots of the spliceosome: Structural insights into a dynamic ribonucleoprotein machine. Nature Structural & Molecular Biology, 24(10), 791–799. https://doi.org/10.1038/nsmb.3463.

    Article  CAS  Google Scholar 

  85. Climente-González, H., Porta-Pardo, E., Godzik, A., & Eyras, E. (2017). The functional impact of alternative splicing in Cancer. Cell Reports, 20(9), 2215–2226. https://doi.org/10.1016/j.celrep.2017.08.012.

    Article  CAS  PubMed  Google Scholar 

  86. Hoyos, L. E., & Abdel-Wahab, O. (2018). Cancer-specific splicing changes and the potential for splicing-derived neoantigens. Cancer Cell, 34(2), 181–183. https://doi.org/10.1016/j.ccell.2018.07.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Anczuków, O., & Krainer, A. R. (2016). Splicing-factor alterations in cancers. RNA, 22(9), 1285–1301. https://doi.org/10.1261/rna.057919.116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Anczuków, O., Rosenberg, A. Z., Akerman, M., Das, S., Zhan, L., Karni, R., Muthuswamy, S. K., & Krainer, A. R. (2012). The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nature Structural & Molecular Biology, 19(2), 220–228. https://doi.org/10.1038/nsmb.2207.

    Article  CAS  Google Scholar 

  89. Karni, R., de Stanchina, E., Lowe, S. W., Sinha, R., Mu, D., & Krainer, A. R. (2007). The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nature Structural & Molecular Biology, 14(3), 185–193. https://doi.org/10.1038/nsmb1209.

    Article  CAS  Google Scholar 

  90. Ghigna, C., Giordano, S., Shen, H., Benvenuto, F., Castiglioni, F., Comoglio, P. M., Green, M. R., Riva, S., & Biamonti, G. (2005). Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Molecular Cell, 20(6), 881–890. https://doi.org/10.1016/j.molcel.2005.10.026.

    Article  CAS  PubMed  Google Scholar 

  91. Ge, K., DuHadaway, J., Du, W., Herlyn, M., Rodeck, U., & Prendergast, G. C. (1999). Mechanism for elimination of a tumor suppressor: Aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma. Proceedings of the National Academy of Sciences of the United States of America, 96(17), 9689–9694. https://doi.org/10.1073/pnas.96.17.9689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Scheper, G. C., Parra, J. L., Wilson, M., Van Kollenburg, B., Vertegaal, A. C., Han, Z. G., et al. (2003). The N and C termini of the splice variants of the human mitogen-activated protein kinase-interacting kinase Mnk2 determine activity and localization. Molecular and Cellular Biology, 23(16), 5692–5705. https://doi.org/10.1128/mcb.23.16.5692-5705.2003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chen, L., Luo, C., Shen, L., Liu, Y., Wang, Q., Zhang, C., Guo, R., Zhang, Y., Xie, Z., Wei, N., Wu, W., Han, J., & Feng, Y. (2017). SRSF1 prevents DNA damage and promotes tumorigenesis through regulation of DBF4B pre-mRNA splicing. Cell Reports, 21(12), 3406–3413. https://doi.org/10.1016/j.celrep.2017.11.091.

    Article  CAS  PubMed  Google Scholar 

  94. Dvinge, H., Kim, E., Abdel-Wahab, O., & Bradley, R. K. (2016). RNA splicing factors as oncoproteins and tumour suppressors. Nature Reviews. Cancer, 16(7), 413–430. https://doi.org/10.1038/nrc.2016.51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Urbanski, L. M., Leclair, N., & Anczuków, O. (2018). Alternative-splicing defects in cancer: Splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics. Wiley Interdisciplinary Reviews RNA, 9(4), e1476. https://doi.org/10.1002/wrna.1476.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Obeng, E. A., Stewart, C., & Abdel-Wahab, O. (2019). Altered RNA processing in cancer pathogenesis and therapy. Cancer Discovery, 9(11), 1493–1510. https://doi.org/10.1158/2159-8290.CD-19-0399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Dutertre, M., Chakrama, F. Z., Combe, E., Desmet, F. O., Mortada, H., Polay Espinoza, M., Gratadou, L., & Auboeuf, D. (2014). A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors. Nature Communications, 5, 3395. https://doi.org/10.1038/ncomms4395.

    Article  CAS  PubMed  Google Scholar 

  98. Vorlová, S., Rocco, G., Lefave, C. V., Jodelka, F. M., Hess, K., Hastings, M. L., et al. (2011). Induction of antagonistic soluble decoy receptor tyrosine kinases by intronic polyA activation. Molecular Cell, 43(6), 927–939. https://doi.org/10.1016/j.molcel.2011.08.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lee, S. H., Singh, I., Tisdale, S., Abdel-Wahab, O., Leslie, C. S., & Mayr, C. (2018). Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia. Nature, 561(7721), 127–131. https://doi.org/10.1038/s41586-018-0465-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Graber, J. H., Nazeer, F. I., Yeh, P. C., Kuehner, J. N., Borikar, S., Hoskinson, D., & Moore, C. L. (2013). DNA damage induces targeted, genome-wide variation of poly(A) sites in budding yeast. Genome Research, 23(10), 1690–1703. https://doi.org/10.1101/gr.144964.112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Davidson, L., Muniz, L., & West, S. (2014). 3′ end formation of pre-mRNA and phosphorylation of Ser2 on the RNA polymerase II CTD are reciprocally coupled in human cells. Genes & Development, 28(4), 342–356. https://doi.org/10.1101/gad.231274.113.

    Article  CAS  Google Scholar 

  102. Dubbury, S. J., Boutz, P. L., & Sharp, P. A. (2018). CDK12 regulates DNA repair genes by suppressing intronic polyadenylation. Nature, 564(7734), 141–145. https://doi.org/10.1038/s41586-018-0758-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Quereda, V., Bayle, S., Vena, F., Frydman, S. M., Monastyrskyi, A., Roush, W. R., et al. (2019). Therapeutic targeting of CDK12/CDK13 in triple-negative breast cancer. Cancer Cell, 36(5), 545–558.e7. https://doi.org/10.1016/j.ccell.2019.09.004.

    Article  CAS  PubMed  Google Scholar 

  104. Tian, B., Hu, J., Zhang, H., & Lutz, C. S. (2005). A large-scale analysis of mRNA polyadenylation of human and mouse genes. Nucleic Acids Research, 33(1), 201–212. https://doi.org/10.1093/nar/gki158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Venters, C. C., Oh, J. M., Di, C., So, B. R., & Dreyfuss, G. (2019). U1 snRNP telescripting: Suppression of premature transcription termination in introns as a new layer of gene regulation. Cold Spring Harbor Perspectives in Biology, 11(2). https://doi.org/10.1101/cshperspect.a032235.

  106. Tian, B., & Manley, J. L. (2017). Alternative polyadenylation of mRNA precursors. Nature Reviews. Molecular Cell Biology, 18(1), 18–30. https://doi.org/10.1038/nrm.2016.116.

    Article  CAS  PubMed  Google Scholar 

  107. Sandberg, R., Neilson, J. R., Sarma, A., Sharp, P. A., & Burge, C. B. (2008). Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites. Science, 320(5883), 1643–1647. https://doi.org/10.1126/science.1155390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Mayr, C., & Bartel, D. P. (2009). Widespread shortening of 3'UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell, 138(4), 673–684. https://doi.org/10.1016/j.cell.2009.06.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Rosenwald, A., Wright, G., Wiestner, A., Chan, W. C., Connors, J. M., Campo, E., Gascoyne, R. D., Grogan, T. M., Muller-Hermelink, H. K., Smeland, E. B., Chiorazzi, M., Giltnane, J. M., Hurt, E. M., Zhao, H., Averett, L., Henrickson, S., Yang, L., Powell, J., Wilson, W. H., Jaffe, E. S., Simon, R., Klausner, R. D., Montserrat, E., Bosch, F., Greiner, T. C., Weisenburger, D. D., Sanger, W. G., Dave, B. J., Lynch, J. C., Vose, J., Armitage, J. O., Fisher, R. I., Miller, T. P., LeBlanc, M., Ott, G., Kvaloy, S., Holte, H., Delabie, J., & Staudt, L. M. (2003). The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell, 3(2), 185–197.

    Article  CAS  PubMed  Google Scholar 

  110. Xia, Z., Donehower, L. A., Cooper, T. A., Neilson, J. R., Wheeler, D. A., Wagner, E. J., & Li, W. (2014). Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3'-UTR landscape across seven tumour types. Nature Communications, 5, 5274. https://doi.org/10.1038/ncomms6274.

    Article  CAS  PubMed  Google Scholar 

  111. Begik, O., Oyken, M., Cinkilli Alican, T., Can, T., & Erson-Bensan, A. E. (2017). Alternative polyadenylation patterns for novel gene discovery and classification in Cancer. Neoplasia, 19(7), 574–582. https://doi.org/10.1016/j.neo.2017.04.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Akman, B. H., Can, T., & Erson-Bensan, A. E. (2012). Estrogen-induced upregulation and 3'-UTR shortening of CDC6. Nucleic Acids Research, 40(21), 10679–10688. https://doi.org/10.1093/nar/gks855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Akman, H. B., Oyken, M., Tuncer, T., Can, T., & Erson-Bensan, A. E. (2015). 3 ' UTR shortening and EGF signaling: Implications for breast cancer. Human Molecular Genetics, 24(24), 6910–6920. https://doi.org/10.1093/hmg/ddv391.

    Article  CAS  PubMed  Google Scholar 

  114. Miles, W. O., Lembo, A., Volorio, A., Brachtel, E., Tian, B., Sgroi, D., Provero, P., & Dyson, N. (2016). Alternative polyadenylation in triple-negative breast tumors allows NRAS and c-JUN to bypass PUMILIO posttranscriptional regulation. Cancer Research, 76(24), 7231–7241. https://doi.org/10.1158/0008-5472.CAN-16-0844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Chen, M., Lyu, G., Han, M., Nie, H., Shen, T., Chen, W., Niu, Y., Song, Y., Li, X., Li, H., Chen, X., Wang, Z., Xia, Z., Li, W., Tian, X. L., Ding, C., Gu, J., Zheng, Y., Liu, X., Hu, J., Wei, G., Tao, W., & Ni, T. (2018). 3' UTR lengthening as a novel mechanism in regulating cellular senescence. Genome Research, 28, 285–294. https://doi.org/10.1101/gr.224451.117.

    Article  CAS  PubMed Central  Google Scholar 

  116. Jia, Q., Nie, H., Yu, P., Xie, B., Wang, C., Yang, F., et al. (2019). HNRNPA1-mediated 3' UTR length changes of HN1 contributes to cancer- and senescence-associated phenotypes. Aging (Albany NY), 11(13), 4407–4437. https://doi.org/10.18632/aging.102060.

    Article  CAS  Google Scholar 

  117. Matallanas, D., Birtwistle, M., Romano, D., Zebisch, A., Rauch, J., von Kriegsheim, A., & Kolch, W. (2011). Raf family kinases: Old dogs have learned new tricks. Genes & Cancer, 2(3), 232–260. https://doi.org/10.1177/1947601911407323.

    Article  CAS  Google Scholar 

  118. Cantwell-Dorris, E. R., O'Leary, J. J., & Sheils, O. M. (2011). BRAFV600E: Implications for carcinogenesis and molecular therapy. Molecular Cancer Therapeutics, 10(3), 385–394. https://doi.org/10.1158/1535-7163.MCT-10-0799.

    Article  CAS  PubMed  Google Scholar 

  119. Kim, A., & Cohen, M. S. (2016). The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma. Expert Opinion on Drug Discovery, 11(9), 907–916. https://doi.org/10.1080/17460441.2016.1201057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Marranci, A., Jiang, Z., Vitiello, M., Guzzolino, E., Comelli, L., Sarti, S., Lubrano, S., Franchin, C., Echevarría-Vargas, I., Tuccoli, A., Mercatanti, A., Evangelista, M., Sportoletti, P., Cozza, G., Luzi, E., Capobianco, E., Villanueva, J., Arrigoni, G., Signore, G., Rocchiccioli, S., Pitto, L., Tsinoremas, N., & Poliseno, L. (2017). The landscape of BRAF transcript and protein variants in human cancer. Molecular Cancer, 16(1), 85. https://doi.org/10.1186/s12943-017-0645-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Marranci, A., Tuccoli, A., Vitiello, M., Mercoledi, E., Sarti, S., Lubrano, S., Evangelista, M., Fogli, A., Valdes, C., Russo, F., Monte, M. D., Caligo, M. A., Pellegrini, M., Capobianco, E., Tsinoremas, N., & Poliseno, L. (2015). Identification of BRAF 3'UTR isoforms in melanoma. The Journal of Investigative Dermatology, 135(6), 1694–1697. https://doi.org/10.1038/jid.2015.47.

    Article  CAS  PubMed  Google Scholar 

  122. Pardoll, D. M. (2012). The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews. Cancer, 12(4), 252–264. https://doi.org/10.1038/nrc3239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Shi, Y. (2018). Regulatory mechanisms of PD-L1 expression in cancer cells. Cancer Immunology, Immunotherapy, 67(10), 1481–1489. https://doi.org/10.1007/s00262-018-2226-9.

    Article  CAS  PubMed  Google Scholar 

  124. Kataoka, K., Shiraishi, Y., Takeda, Y., Sakata, S., Matsumoto, M., Nagano, S., Maeda, T., Nagata, Y., Kitanaka, A., Mizuno, S., Tanaka, H., Chiba, K., Ito, S., Watatani, Y., Kakiuchi, N., Suzuki, H., Yoshizato, T., Yoshida, K., Sanada, M., Itonaga, H., Imaizumi, Y., Totoki, Y., Munakata, W., Nakamura, H., Hama, N., Shide, K., Kubuki, Y., Hidaka, T., Kameda, T., Masuda, K., Minato, N., Kashiwase, K., Izutsu, K., Takaori-Kondo, A., Miyazaki, Y., Takahashi, S., Shibata, T., Kawamoto, H., Akatsuka, Y., Shimoda, K., Takeuchi, K., Seya, T., Miyano, S., & Ogawa, S. (2016). Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers. Nature, 534(7607), 402–406. https://doi.org/10.1038/nature18294.

    Article  CAS  PubMed  Google Scholar 

  125. Hassounah, N. B., Malladi, V. S., Huang, Y., Freeman, S. S., Beauchamp, E. M., Koyama, S., Souders, N., Martin, S., Dranoff, G., Wong, K. K., Pedamallu, C. S., Hammerman, P. S., & Akbay, E. A. (2019). Identification and characterization of an alternative cancer-derived PD-L1 splice variant. Cancer Immunology, Immunotherapy, 68(3), 407–420. https://doi.org/10.1007/s00262-018-2284-z.

    Article  CAS  PubMed  Google Scholar 

  126. Mahoney, K. M., Shukla, S. A., Patsoukis, N., Chaudhri, A., Browne, E. P., Arazi, A., Eisenhaure, T. M., Pendergraft III, W. F., Hua, P., Pham, H. C., Bu, X., Zhu, B., Hacohen, N., Fritsch, E. F., Boussiotis, V. A., Wu, C. J., & Freeman, G. J. (2019). A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression. Cancer Immunology, Immunotherapy, 68(3), 421–432. https://doi.org/10.1007/s00262-018-2282-1.

    Article  CAS  PubMed  Google Scholar 

  127. Audrito, V., Serra, S., Stingi, A., Orso, F., Gaudino, F., Bologna, C., et al. (2017). PD-L1 up-regulation in melanoma increases disease aggressiveness and is mediated through miR-17-5p. Oncotarget, 8(9), 15894–15911. https://doi.org/10.18632/oncotarget.15213.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Xie, W. B., Liang, L. H., Wu, K. G., Wang, L. X., He, X., Song, C., Wang, Y. Q., & Li, Y. H. (2018). MiR-140 expression regulates cell proliferation and targets PD-L1 in NSCLC. Cellular Physiology and Biochemistry, 46(2), 654–663. https://doi.org/10.1159/000488634.

    Article  CAS  PubMed  Google Scholar 

  129. Puente, X. S., Beà, S., Valdés-Mas, R., Villamor, N., Gutiérrez-Abril, J., Martín-Subero, J. I., Munar, M., Rubio-Pérez, C., Jares, P., Aymerich, M., Baumann, T., Beekman, R., Belver, L., Carrio, A., Castellano, G., Clot, G., Colado, E., Colomer, D., Costa, D., Delgado, J., Enjuanes, A., Estivill, X., Ferrando, A. A., Gelpí, J. L., González, B., González, S., González, M., Gut, M., Hernández-Rivas, J. M., López-Guerra, M., Martín-García, D., Navarro, A., Nicolás, P., Orozco, M., Payer, Á. R., Pinyol, M., Pisano, D. G., Puente, D. A., Queirós, A. C., Quesada, V., Romeo-Casabona, C. M., Royo, C., Royo, R., Rozman, M., Russiñol, N., Salaverría, I., Stamatopoulos, K., Stunnenberg, H. G., Tamborero, D., Terol, M. J., Valencia, A., López-Bigas, N., Torrents, D., Gut, I., López-Guillermo, A., López-Otín, C., & Campo, E. (2015). Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature, 526(7574), 519–524. https://doi.org/10.1038/nature14666.

    Article  CAS  PubMed  Google Scholar 

  130. Wang, W., Sun, J., Li, F., Li, R., Gu, Y., Liu, C., Yang, P., Zhu, M., Chen, L., Tian, W., Zhou, H., Mao, Y., Zhang, L., Jiang, J., Wu, C., Hua, D., Chen, W., Lu, B., Ju, J., & Zhang, X. (2012). A frequent somatic mutation in CD274 3'-UTR leads to protein over-expression in gastric cancer by disrupting miR-570 binding. Human Mutation, 33(3), 480–484. https://doi.org/10.1002/humu.22014.

    Article  CAS  PubMed  Google Scholar 

  131. Desrosiers, R., Friderici, K., & Rottman, F. (1974). Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proceedings of the National Academy of Sciences of the United States of America, 71(10), 3971–3975. https://doi.org/10.1073/pnas.71.10.3971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Dominissini, D., Moshitch-Moshkovitz, S., Schwartz, S., Salmon-Divon, M., Ungar, L., Osenberg, S., Cesarkas, K., Jacob-Hirsch, J., Amariglio, N., Kupiec, M., Sorek, R., & Rechavi, G. (2012). Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature, 485(7397), 201–206. https://doi.org/10.1038/nature11112.

    Article  CAS  PubMed  Google Scholar 

  133. Bushkin, G. G., Pincus, D., Morgan, J. T., Richardson, K., Lewis, C., Chan, S. H., Bartel, D. P., & Fink, G. R. (2019). m6A modification of a 3' UTR site reduces RME1 mRNA levels to promote meiosis. Nature Communications, 10(1), 3414. https://doi.org/10.1038/s41467-019-11232-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Zhang, C., Samanta, D., Lu, H., Bullen, J. W., Zhang, H., Chen, I., He, X., & Semenza, G. L. (2016). Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA. Proceedings of the National Academy of Sciences of the United States of America, 113(14), E2047–E2056. https://doi.org/10.1073/pnas.1602883113.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Erson-Bensan, A. E., & Can, T. (2016). Alternative Polyadenylation: Another foe in cancer. Molecular Cancer Research. https://doi.org/10.1158/1541-7786.MCR-15-0489.

  136. Gruber, A. J., & Zavolan, M. (2019). Alternative cleavage and polyadenylation in health and disease. Nature Reviews. Genetics, 20(10), 599–614. https://doi.org/10.1038/s41576-019-0145-z.

    Article  CAS  PubMed  Google Scholar 

  137. Shulman, E. D., & Elkon, R. (2019). Cell-type-specific analysis of alternative polyadenylation using single-cell transcriptomics data. Nucleic Acids Research, 47(19), 10027–10039. https://doi.org/10.1093/nar/gkz781.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Steber, H. S., Gallante, C., O'Brien, S., Chiu, P. L., & Mangone, M. (2019). The C. elegans 3' UTRome v2 resource for studying mRNA cleavage and polyadenylation, 3'-UTR biology, and miRNA targeting. Genome Research, 29(12), 2104–2116. https://doi.org/10.1101/gr.254839.119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The author sincerely apologizes to colleagues whose important work could not be cited in this review article because of space limitations, and thanks the laboratory members for critical reading of the manuscript. Funding for our laboratory’s work on 3′UTRs was from TUBITAK and METU.

Author information

Authors and Affiliations

  1. Department of Biological Sciences and Cancer Systems Biology Laboratory, Middle East Technical University (METU, ODTU), Dumlupinar Blv No: 1, Universiteler Mah, 06800, Ankara, Turkey

    Ayse Elif Erson-Bensan

Authors
  1. Ayse Elif Erson-Bensan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ayse Elif Erson-Bensan.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Erson-Bensan, A.E. RNA-biology ruling cancer progression? Focus on 3′UTRs and splicing. Cancer Metastasis Rev 39, 887–901 (2020). https://doi.org/10.1007/s10555-020-09884-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-020-09884-9

Keywords

Search

Navigation